Pancreatic cancer is the fourth to fifth leading cause of cancer-related death in the Western world. The prognosis for diagnosed patients is poor with an overall 5-years survival rate less than 5%, 12 month survival rate of 10%, and a median survival time of approximately 3-5 months after tumour detection. Major reasons for this poor outcome are the inability to diagnose pancreatic cancer at an early stage because of the lack of specific symptoms, inaccessible location of the pancreas, and an early occurrence of metastatic disease. To date, current radiation and chemotherapy regimens have not achieved significant improvement in the long term survival of pancreatic cancer patients, emphasising the importance of developing novel combination therapies more effective against advanced stages of this disease.
The causes of pancreatic cancer are not yet well understood but increasing attention has been directed towards the role of growth factors in the pathogenesis of the disease. Numerous growth factors and their receptors are over-expressed during the progression of pancreatic cancer such as EGF, PDGF and VEGF, suggesting the importance in evaluating selective inhibitor of receptor tyrosine kinase in this disease.
Gemcitabine (2′,2′,-dofluoro-2′,-deoxycytidine) is a nucleoside analog of deoxycytidine marketed as GEMZAR™ that interferes with DNA synthesis through inhibition of ribonucleotide reductase and competition with dCTP for incorporation into DNA. It is currently the treatment of reference for several cancers such as pancreatic cancers and it is associated with radiotherapy. However, treatment protocol with gemcitabine alone has little influence on patients' survival.
Thus, as of today, there is no cure for pancreatic cancer.
Much research is being performed to find compounds that would either act in synergy or abolish gemcitabine resistance observed in numerous cancers. Despite numerous efforts, data obtained so far suggested the implication of the Bc12 gene family in pancreatic cancer resistance to gemcitabine but has not led to significant improvement of treatment protocols. Also, several attempts to find effective combination therapy has been described but are not successful. For example anti-angiogenesis compounds have been co-administered with gemcitabine and no improvement in survival have been observed so far.
AB1010 (Masitinib) is a novel tyrosine kinase inhibitor developed by AB Science part of 2-aminoarylthiazoles derivatives that targets c-Kit and PDGFR13 receptors, and which are the subject matter of WO 2004/014903. AB1010 is currently being evaluated in clinical trials in number of malignancies and so far the results are very encouraging.
The pre-clinical data reported herein clearly show that AB1010 reverse resistance of pancreatic tumour cell lines to the gemcitabine. These results show that AB1010 has great potential as combination therapy in gemcitabine treated patients for several cancers such as non-small cell lung cancer, pancreatic, bladder, breast and ovarian cancer as well as advanced biliary tract cancers. We also found that AB1010 sensitize the action of antimitotics such as docetaxel. Although the exact mechanism of action of 2-aminoarylthiazoles which are C-KIT/PDGF-R inhibitors as defined here below is not yet fully elucidated, we discovered that theses tyrosine kinase inhibitors are able to block the FAK pathway in the context of cancer cells resisting to conventional gemcitabine or docetaxel treatment. Blocking the FAK pathway might explain the sensitization of chemotherapeutic agents as tumor cells loss their adherence properties impeding cells migration. In any case, this discovery also imply that cancer cells treated with the above compounds are less prone to metastasis.
Thus, we provide here for the first time a combined treatment of solid cancers with at least one antimetabolite, such as gemcitabine or docetaxel, and a tyrosine kinase inhibitor selected from 2-aminoarylthiazole and 2-aminoaryloxazole allowing to reverse resistance as well as sensitize cancer cells to standard chemotherapy.